In this episode, Neutrophil visits an infected hair root where the hair cells are enslaved by Acne Bacteria. Neutrophil saves young Hair Matrix Cell who tries to fight the Acne Bacteria, but the Acne Bacteria injure Neutrophil and throw him and Hair Matrix Cell into the pit. In the pit, Hair Matrix Cell tells the story of how the hair cells were enslaved by Acne Bacteria when a pimple was formed before showing Neutrophil the stacks of dead neutrophils. This motivates Neutrophil to eliminate the Acne Bacteria, so after coming back up, he battles against the Acne King. As Neutrophil struggles to defeat the Acne King, Hair Matrix Cell motivates the other hair cells to not give up, leading them to raise the sebum levels in an attempt to drown the Acne King. The Acne King tries to flee but moves too slowly, allowing Neutrophil to kill him. Neutrophil later re-emerges from a sebum pipe after all the Acne Bacteria are killed, to the relief of the other neutrophils and hair cells.
Even though the episode gives a good overview of what acne is, particularly that bacteria are involved, that is only part of the story. There are many factors that contribute to the development of acne. In fact, the presence of white blood cells such as neutrophils is not only insufficient for curing acne but can also worsen acne. In this blog post, I will explain what acne is, how it develops in real life and how it can be treated.
What is sebum and how is it produced?
Sebum is an oily substance that is made up of many different types of lipids or fats and various antimicrobial substances. It is released from sebaceous glands in the skin to keep the skin moist, preventing it from drying out, and to kill pathogens residing in the skin. The sebaceous glands are part of the pilosebaceous unit along with the hair follicle and hair shaft which are created by dividing hair matrix cells. The pilosebaceous units tend to be mostly found in the face, neck, chest and upper back.
Sebocytes in the sebaceous gland create the lipids that make up sebum. Sebocytes start off undifferentiated in the outer regions of the sebaceous gland. As they move towards the centre of the gland, they become more differentiated and produce lipids, filling the cell up in the process. At the centre of the sebaceous gland, mature sebocytes (represented by elderly Sebaceous Gland Cell in the episode) undergo cell death and break down, releasing the lipids that are incorporated in sebum.
What is acne?
Acne, formally known as acne vulgaris, is a chronic inflammatory disease of the pilosebaceous unit. It afflicts a lot of people, particularly those undergoing puberty. Over 95% boys and 85% girls experience acne in their teenage years with 50% of them continuing to have acne in adulthood. Acne can also leave scars in up to 95% patients as a result of fibrous tissue healing over damaged skin.
Acne can have a profound effect on a person’s social status and mental state. People with acne are more likely to experience discomfort, embarrassment, low self-esteem, and shame, wanting to cover up their acne in social settings. People with acne are also more likely to have psychological problems, developing stress, anxiety, depression and suicidal thoughts. They can experience a quality of life that is just as bad as patients with other chronic diseases such as asthma, epilepsy, back pain and arthritis.
There are four aspects that contribute to the development of acne.
Increased sebum production
Puberty is associated with increased production of androgens such as testosterone. Androgens increase sebum production from the sebaceous gland, resulting in an excessive amount of sebum being generated. The lipid composition of sebum also changes, with more monounsaturated fatty acids and lipoperoxides present in sebum. These lipids promote skin cell proliferation and inflammation, two other processes that contribute to the development of acne.
Excessive skin cell proliferation
Androgens also promote the proliferation of skin cells, leading to skin cells dividing too quickly. These skin cells do not have time to mature and are tightly bound to each other, making it more difficult to shed from skin.
The tightly-bound skin cells form a keratin plug that blocks the hair follicle, creating a microcomedone or “micro-pimple” that cannot be seen with the naked eye. The microcomedone can enlarge as keratin and sebum continue to accumulate, establishing a visible, closed comedone or pimple. These are known as whiteheads due to the white colour of the pimples. Continual accumulation of keratin and sebum can open the closed comedone, becoming an open comedone or pimple. These are known as blackheads due to the oxidation of lipids and melanin, making the pimple black.
Propionibacterium acnes in the hair follicle
| Schematic | Microscopic | Anime |
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The Acne Bacteria in the episode are formally known as Propionibacterium acnes (or Cutibacterium acnes, though I’ll use the former name for this blog post). P. acnes is a Gram-positive, rod-shaped bacterium that normally resides in the skin. It is a facultative anaerobe, able to grow with or without oxygen. However, it prefers to grow in an anaerobic (i.e., no oxygen), lipid-rich environment such as inside a comedone. P. acnes produces a lipase enzyme that breaks down triglycerides in sebum into glycerol and fatty acids, using them to nourish itself. This is the reason why the Acne King was able to heal himself with sebum in the episode. As a result, P. acnes is able to proliferate inside the comedone. This pushes the walls of the comedone until it breaks, spreading the bacteria into surrounding tissue to promote inflammation.
Inflammation
Inflammation starts when white blood cells such as lymphocytes, neutrophils and macrophages detect P. acnes in the surrounding tissue. They release a variety of cytokines such as IL-1b, IL-8 and TNF-a to stimulate inflammation. Inflammation can turn a comedone into an inflammatory lesion such as papules, pustules and nodules or cysts. These inflammatory lesions are often large and filled with pus containing dead white blood cells, particularly neutrophils.
How is acne treated?
In the episode, the hair cells raised the sebum levels in an attempt to drown the Acne King, allowing Neutrophil to kill him. Other neutrophils also arrived at the pimple to eliminate the Acne Bacteria, liberating the hair follicle. In reality, acne is treated not with the actions of hair cells and white blood cells but with drugs that target different parts of acne development. Here are some of the drugs that are given alone or in combination to treat acne.
Topical retinoids
Topical retinoids such as tretinoin, adapalene and tazarotene are vitamin A derivatives that bind to retinoic acid and retinoid X receptors in skin cells. They exert a variety of effects to ameliorate acne. They inhibit the proliferation and adhesion of skin cells, allowing them to be shed more easily from skin. Topical retinoids also reduce sebum production and inhibit inflammation. As a result of these processes, topical retinoids can break down existing comedones and prevent new ones from appearing. They also open up clogged pores, making it easier for other drugs such as antimicrobials to access the inside of the comedone. These drugs appear as creams that are applied to the skin.
Topical antimicrobials
Benzoyl peroxide is the main topical antimicrobial used to treat acne. Applied as a cream to the skin, it has a wide range of effects. Firstly, it releases free radicals to degrade bacterial proteins, killing bacteria. Benzoyl peroxide can also impede inflammation, break down keratin to lyse comedones and promote wound healing.
Antibiotics
Topical and oral antibiotics can target bacteria in the skin and pilosebaceous unit, particularly P. acnes. They are designed to impede the bacteria’s ability to divide, leading to their elimination. They can also inhibit inflammation, particularly in moderate to severe acne where inflammatory lesions appear. Erythromycin and clindamycin are commonly applied on the skin while tetracyclines such as tetracycline, doxycycline and minocycline are taken orally.
Oral isotretinoin
Isotretinoin is a strong retinoid drug that, taken orally, targets all four areas of acne development. It is mainly given to patients with moderate to severe acne, particularly those that are developing scars from acne. Isotretinoin mainly reduces sebum production by impeding cell proliferation among sebocytes and stimulating its cell death. It also reduces P. acnes concentrations by depriving the bacterium of sebum, breaks down comedones by inhibiting the proliferation of skin epithelial cells and promoting the shedding of skin and inhibits inflammation.
Oral isotretinoin can cure 85% of acne cases, but it has numerous side-effects, particularly severe ones such as depression. Hence, prescription of the drug has to be closely supervised by a dermatologist who has to inform the patient about the benefits and draw-backs of the drug. Isotretinoin is also a teratogen, causing birth defects and abnormalities in babies. Hence, isotretinoin cannot be given to women who are pregnant or are planning to become pregnant.
Conclusion
Acne is a chronic inflammatory disease involving many different factors. Blockage of the hair follicle by over-proliferating skin cells combined with increased sebum production establishes a comedone or pimple and provides an environment where Acne Bacteria, formally known as P. acnes, can thrive. The propagation of P. acnes can spill over to surrounding tissue, leading to inflammation which can produce an inflammatory lesion and potentially scarring. Even though acne can have a profound effect on a person’s life, there are many drugs that can be used to treat the different parts of acne. These treatments will not only eliminate the Acne Bacteria but also promote conditions where the skin is able to heal from acne.
In the next blog post, I will talk about dengue fever and the roles that mast cells and histamine can play in reducing (or increasing) the severity of dengue fever. See you then!
References
There are a few reviews and websites that go over the clinical and treatment aspects of acne. The most useful review I found was written by Tuchayi et al. (2015) for Nature Reviews Disease Primers. This review not only goes into the treatment of acne in a great amount of detail but it also gives an excellent description of how acne develops from a biological standpoint.
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